Friday, 31 August 2012

Today is Maria Espasandin's last day in our group! She has worked as our clinical research manager for over 10 years. Dependable, thorough, highly-skilled and an asset we are can't afford to be losing. Ask Maria to get a trial or study protocol written and through ethics and bingo it is done. Maria was also the person responsible for arranging our annual research days. We are going to find it difficult replacing Maria's skills. We hope the grass is greener on the pharma side if not you can always change your mind and come back.

PURPOSE: The efficacy of statins in combination with interferon therapy in patients with multiple sclerosis
(MS) is reviewed. METHODS: A systematic literature search was conducted
through September 2011 to identify randomized controlled trials that
evaluated the effect of combination statin-interferon therapy compared
with interferon therapy alone in patients with MS. Trials had to report
at least one of the following outcomes of interest: clinical relapse
rate, disease progression, or Expanded Disability Status Scale (EDSS)
score.

RESULTS: Four unique trials were
included in the analysis (n = 463 subjects; range of follow-up, 9-24
months). All trials evaluated patients
with relapsing-remitting MS (RRMS). Most trials enrolled patients taking
interferon beta therapy either twice or three times weekly. The mean
baseline EDSS scores ranged from 1.2 to 3.4. Evaluated statins included
simvastatin and atorvastatin. No significant difference was found
between the statin and control groups in the incident rate ratio for
clinical relapse (0.72; 95% confidence interval [CI], 0.17 to 3.11),
risk of relapse (relative risk [RR], 0.99; 95% CI, 0.53 to 1.85],
disease progression (RR, 1.31; 95% CI, 0.73 to 2.36), or difference in
the change in the EDSS score from baseline (weighted mean difference,
-0.06; 95% CI, -0.30 to 0.19).

CONCLUSION A meta-analysis revealed that
the addition of statins to interferon therapy did not significantly
influence the relapse risk, disease progression, or EDSS scores in
patients with RRMS.

The
conclusions say it all. There is no good evidence that statins really
make an influence on RRMS by themselves and appear to add nothing when
used as an add-on to beta interferon.

BACKGROUND: The increasing number of effective therapies to treat
MS raises ethical concerns for the use of placebo
in clinical trials, suggesting that new clinical trial design strategies
are needed.

OBJECTIVES: To evaluate time to first relapse as an endpoint for MS clinical trials.

METHODS: A
recently-developed model fitting the distribution of time to first
relapse in MS was used for simulations estimating the sample sizes of
trials using this as an outcome, and for comparison with the size of
trials using the annualized relapse rate (ARR) as the primary outcome.

RESULTS:
Trials based on time to first relapse were feasible, requiring sample
sizes that were similar or even smaller than if the study was based on
ARR instead. In the case of low ARR (0.4 relapses/year), as is expected
in future trials, the 1-year trials designed to detect a treatment
effect of 30%, with 90% power, require fewer MSers when based on time
to first relapse (470 MSers/arm) than if based on ARR (540
MSers/arm).

CONCLUSIONS:
Our simulations show that time to first relapse is not less powerful
than ARR in MS trials; thus, this measure would be a potentially useful
primary outcome offering the advantage of an ethically sound design, as
the MSers randomized to placebo can then switch to the active drug,
once they relapse. A potential drawback is the loss of information for
other endpoints collected at fixed time points.

"This analysis supports what we have been saying for sometime we need to be more imaginative in how
we undertake trials so that they can speed up the thoughput of new
drugs and expose fewer MSers to trial conditions. Let's hope the regulators see the advantage of this!"

Materials and Methods:Two hundred fifty-nine patients with MS were followed with the Multiple Sclerosis Impact Scale (MSIS-29) before and for 1and 6 months after treatment of extracranial internal jugular vein and azygos vein stenoses and occlusions using venous angioplasty, as well as stent placement in 2.5% of patients. Before treatment, the patients were tested with magnetic resonance (MR) venography and flow quantification.

Results: We found statistically significant improvements in the MSIS-29 scores (P < .01) at both 1 and 6 months. At 1 and 6 months, 67.9% and 53.6% were improved on the physical scale, respectively, and 53.0% and 44.4% were improved on the psychological scale, respectively. Women showed greater improvement than did men on the physical scale at 6 months (P = .01). Patients with primary progressive MS (PPMS) showed less improvement than did those with relapsing-remitting MS (RRMS) on the psychological scale at 1 month, and venoplasty treatment of more vein sites versus fewer vein sites showed greater improvement on the physical scale at both 1 and 6 months. Fifteen patients (6.3%) reported recurrent symptoms after clinical improvement and were treated again. There was one serious adverse event, a deep venous thrombosis at the catheter insertion site, which resolved with treatment.

Conclusions :Endovascular treatment of CCSVI in patients with MS appears to be a safe procedure resulting in significant clinical improvement.

Well you can all read and so the conclusions say it all. This is not a clinical trial but a retrospective look at people who have had venoplasy and 70% felt better at 1 month after treatment.

Therefore if the trials ongoing look at one month then it should be a breeze to show an effect. But at 6 months only 50% better or no effect/worse. If one looks at 12 months then maybe it is going to be touch and go. The BRAVE DREAMS trial of Zamboni is baseline and 12 months, maybe months too far.

We need to see data from placebo controlled trials. The pro-side should be confident and say "bring it on". Let us hope it works.

This study is by David Hubbard of the Hubbard Foundation, which investigates the vascular component of neurological
disorders, such as Chronic Cerebrospinal Venous Insufficiency. So no conflict of interest in showing CCSVI as a disease entity then :-)

Another
not Campath-related:-) question but perhaps some of the docs has time
to answer - can you tell how much a blood test for Aquaporin-4 would
cost me if I were to cover for it privately - just roughly need to know
if I need to sell my car or something ;-) thanks.

Not
sure why it would cheer us up, we have no real axe to grind with the
Zamboni hypothesis except that we want definative proof the CCSVI
hypothesis has legs, which is increasingly unlikely. We are saddened by
the false hope and resource and human costs that this so called
"eccentric and maverick" (by an A from Cambridge) idea has appeared to
consume.

That MS suceptibility genes are largely immune related
is not new we have known about this for years...therefore it is not
news. The generation of this information has likewise not smelt of roses
along its history.

However if I said I dont think that
progressive MS is not anything to do with autoimmunity this could be
true and this could still require immune related genes in its trigger.
The question is can the vascular protagonists build the fact into their
ideas, with something that is not a shaggy dog hypothesis. This has
always been a problem with the CCSVI story that it brushes many on the
known facts about MS aside.

What
would be required of a white knight in this context? Funding or time
(or both?). I'm willing but whether I'm able is a different matter...
Surely an IV Cladribine trial would be a prime fund raising opp given it
is a generic drug that could be as effective as the many (very
expensive) DMTs. Wouldnt the various MS charities consider this?

As
an aside, we're any results ever gathered from the Oracle trial of Clad
for CIS or was the plug pulled before they could be obtained? Was there
any informal sense of how effective it had been? Prof G?

In this context...
A
consultant neurologists with an iron back with the time and energy to
co-ordinate a safety trial and organise the funding for the trial
(could be MS Charities or Government) and presumably subsequent
licencing. (This is not Prof G).

How
can it be that there isn't a neuro interested in taking this on? A drug
with comparable effectiveness to the newer induction agents,
potentially less side effects and no patent. Surely that's a very
significant potential drug just sat gathering dust or being used in the
odd off-label use? If its safety could be proved, then the neuro
responsible would receive huge plaudits. Back to my earlier question -
does anyone know what happened to the Oracle trial for this drug? Were
any results gathered?

Interesting
that Oracle was CIS. If the results are promising, that's taking early,
aggressive to a new level (i.e. induction treatment at CIS stage). Is
off label IV clad a reasonable strategy for new CISers to consider with
their neuros? If it can be shown to significantly reduce risk of
conversion to MS then it could be extremely important.

Who is responsible for Oracle? Presumably not Merck given they've abandoned oral Clad?

Do
you expect we'll get the results at ECTRIMS? Are we certain this data
is being collated? I can't see why EMS would do this given Oral Clad has
been binned? Safety aside, it will be interesting to see the results.
I'm certainly considering IV Clad off-label - cancer risk or not - now
Alem is off the agenda for the time being.

EMS
has not binned it; they are simply not developing it further. I suspect
if someone came along with the right price they may sell the oral
cladribine portfolio. The buyer would have to do another trial to get
safety data; by the time there is sufficient safety data the patent
would have expired and there would be no window to may their money back.
This is an example why patents and incentives are so important to get
pharma to invest and develop drugs for MS.

This is a rude and unnecessary comment. And you don't even have the guts to put your name to the post.
I hope Prof G does have a lovely meal in Lyon. Why go to Lyon otherwise?
But
the deeper point is this: Prof G and his team don't have to run this
blog. They don't have to be engaged and passionate as they clearly are.
So slagging them off on it is not only counter productive (they might
just stop posting) but it really is pathetic. Yes, you (I) have a crap
disease. Yes, it makes you (me) feel bad. But this isn't Prof G's
fault. So lay off the insults.

Thanks
Iain O. Well said. More sensitive people would see a comment like that
and wonder why we bother. Fortunately we aren't. We totally understand
MSers frustration but slagging off people who really do care is really
not the way to go. Team G actually look forward to the day when MS is
cured and we put ourselves out of a job.
Have no worries, we won't stop posting!

I
agree entirely. This blog is an invaluable source of info and
commentary and the time Prof G and MouseDoctor take to reply to
questions and comments is incredible and generous. As a newly diagnosed
MSer, I'd be completely lost without this site.

Dear Anon 11.15
Saw
Prof G at lunch time and mentioned your comment, it reminded him to
think about food in France as he thinks Lyon will have some nice places
to eat..after all it will be french food.

This study investigated the anti-spasticity potential of Sativex in mice.
Chronic relapsing experimental allergic encephalomyelitis was induced
in adult ABH mice resulting in hind limb spasticity development.
Vehicle, Sativex, and baclofen (as a positive control) were administered and the "stiffness" of limbs assessed by the resistance
force against hind limb flexion. Vehicle alone caused no significant
change in spasticity. Baclofen induced approximately a 40%
peak reduction in spasticity. Sativex dose dependently reduced
spasticity up to approximately a 40% peak
reduction in spasticity. Sativex has the potential to reduce spasticity
in an experimental mouse model of multiple sclerosis
(MS).
Sativex was just as effective as baclofen, providing
supportive evidence for Sativex use in the treatment of spasticity in
MS.

The compounds within Sativex can inhibit spasticity in mice. Well no big shakes there Sativex has been licenced for the treatment of spasticty in Msers for a few years. Yes I know few PCT are funding it because it is too expensive.

Well members of Team G showed that this should happen many moons ago and this study confirms this. The important thing is that mice can not talk to us and so if we can measure benefit, it is not that they are conned because of mind-altering effects, which is a comment often aimed at MSers who take cannabis.

However, the reason why this is important is that the regulators such as the FDA like to see that drugs work in pre-clinical models. This works because it acts on a biology that is involved in the control of spasticity.

CoI: Work was undertaken by Team G and supported by GW Pharmaceuticals the makers of Sativex.Other Members of Team G have generated potentially competing chemicals

BACKGROUND: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest.

OBJECTIVE: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS).

METHODS: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them.

RESULTS: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients' NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load.

CONCLUSION: Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage.

This study looks at neurofilament an internal protein of nerves and examines its content in spinal fluid in people with their first symptoms of MS. This shows that neurofilament notably neurofilament light correlates with the occcurrance of disability, which suggests nerve damage.

In clinic yesterday I was discussing the natalizumab SPMS trial with a SPMSer. It dawned on the MSer, after some discussion, that even if the trial was positive and they were randomised to active agent they would probably not notice any discernible effects at a personal or individual level. The reason for this is that we, the clinicians, don’t expect an effective drug for progressive MS to stop disease progression but to merely slow the rate at which SPMS (or PPMS) progresses. In other words if you were progressing a rate X before the drug you now progress at rate Y, which is simply a slower rate of progression than before. If this was the case you would have no indication the drug was necessarily working. Of course we would like the drug to stop disease progression all together, i.e. stabilise your disease, or hopefully improve your neurological functioning, but this seems unlikely based on observations from other progressive trials and in animal models of SPMS. I have already discussed this issue in some detail before on this blog (see previous survey), but would like to revisit it as I am not sure how to best communicate this information to potential trial participants in a clinical situation. I don't want to MSers volunteering for progressive trials to have unrealistic expectations.

Survey results: neuroprotection. "I am reassured that 55% of MSers expect and effective neuroprotective therapy to stabilise of improve their disability progression; this is a realistic expectation and something that may be ...

A few weeks back one of the readers posted this comment: "Sick of conferences like MS Life. It's pure spin on the scientists' part. Firstly, how about you introduce truly efficacious therapies for progressive MS and then you'll ...

I also spoke to them about the need for better trial designs for progressive MS and described the study design we are promoting using frequent lumbar punctures and neurofilament levels as an outcome measure. They were ...

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for ...

Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients. Study Population: Adult, untreated patients with ...

Giovannoni. Primary progressive MS. ACNR 2012;12(3):9-12. Although PPMS is relatively uncommon it remains a significant clinical problem both diagnostically and therapeutically. PPMS is almost certainly part of the MS ...

Our strategic plan 2012-2016 identifies progressive MS as one of the three key priority areas for MSIF's international MS research going forward (along with paediatric MS and stem cells). This important research area has also ...

But perhaps we should also introduce the Clinical Trials Network (CTN), which was set up specifically for Progressive MSers. This has been reported in some places but may not be common knowledge. As you know all too ...

BACKGROUND: Treatment options for MSers suffering from progressive forms of MS remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various ...

Participants and treatments: 493 MSers with primary or secondary progressive MS were recruited to the study from 27 centres across UK between May 2006 and July 2008. It was a requirement for participants entering the trial ...

Background:It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent.

Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 ...

Challenging the dogma (1): progressive MS and remyelination. In response to a comment concerning dogma in the field of MS, I am going to publish a series of posts that are designed to "challenge the dogma". Dogma: ...

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Holistic Management of MS ver. 7.0

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